PROJECT SUMMARY Surgery is an increasingly common event, impacting over 230 million people annually. Post-surgical pain is variable in severity and duration, but a significant minority (20-30%) of patients experience surgical site pain lasting a year or longer. Such persistent postsurgical pain causes physical and mental suffering and disability, and long exposure to postoperative opioids also puts patients at risk of misuse and addiction. Despite excellent preclinical research into the molecular events involved in the transition of acute to chronic pain after injury, little success at translating these findings to actual prevention of persistent postoperative pain in human patients has been realized. My research program has focused on building a working human model of this transition, by systematic and longitudinal study of pain before, during and after a variety of surgeries. Importantly, we have focused our efforts to identify risk factors to predict those who will actually develop chronic postsurgical pain, rather than those who won?t (70-80%), to make study of this problem more efficient. A crucially important factor in determining the trajectory of post-surgical pain appears to be the capacity for amplification in the circuitry of the pain system, whereby incoming painful input may be increased to the point of intense discomfort. This amplification may be protective in the short term, but dysfunctional if it is excessive or persistent. In our psychophysics lab, we study measures that indicate an excessive (temporal summation of pain, TSP) or prolonged response (painful after sensations, PAS) amplification response of the nervous system in response to standardized pain stimuli. Amplification can also occur at a psychosocial level, where stress, sleep disruption, and catastrophizing (a mental process by which rumination, magnification, and worry increase salience and importance) increase pain perception. Importantly. TSP, PAS, stress, sleep disturbance and catastrophizing are much more prominent in some individuals, and account for a sizeable amount of the variation in postsurgical pain severity (and far more than the surgical extent). We have adapted these tests to easily and non-invasively test this ?amplification phenotype? in individuals BEFORE they have surgery, using modified bedside quantitative sensory tests (QSTs), and brief, validated questionnaires. We propose to use these measures of preoperative amplification phenotype, in order to help target both known and novel non-opioid preventive treatments to those individuals who need them most. This is my area of expertise, as I am an anesthesiologist with formal training in pain neuroscience, psychophysical and psychosocial assessment, and practical experience in conducting translational studies in post-surgical pain. Broadly, my research plan will use this human translational pain model: 1) to speed testing of pain preventive therapies, 2) to develop strategies to reduce pain and opioid use after surgery in high risk individuals, and 3) to forward personalized medicine in the perioperative period. Providing precision medical care and preventing chronic postsurgical pain and opioid use will ultimately improve health care for patients, and lower its cost.